Fingolimod, also known as 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol, is marketed as its hydrochloride salt, and is a sphingosine-1-phosphate receptor (S1P-R) modulator which acts as an immunomodulator by inducing lymphopenia through sequestration of circulating lymphocytes into secondary lymphoid tissues, thus preventing lymphocytes from moving into the transplanted or other affected tissues. Fingolimod (FTY720) is an innovative oral treatment for Relapsing Remitting Multiple Sclerosis (RRMS). Patients with MS display a range of symptoms that arise from demyelination in the central nervous system (CNS), which includes the brain, spinal cord and optic nerves. The destruction of the protective myelin sheath that surrounds nerve cells is thought to be due to the effects of inflammatory T cells.
The first oral S1P-R modulator to be developed, Fingolimod reduces the number of inflammatory T cells in the circulation and CNS and in so doing reduces their potential to damage nerve cells. Thus, in addition to its anti-inflammatory effects in MS, this novel therapy may have the potential to reduce neurodegeneration as well as promote endogenous repair of the CNS. Currently, no marketed treatments for MS can produce remyelination.
JP 11310556, U.S. Pat. No. 5,604,229, U.S. Pat. No. 5,952,316, US 2001/008945, US 2009/082471, WO 00/27798, WO 00/53569, WO 2005/041899, WO 2009/061374, DE 10355169, and CN1528738 disclose 2-amino-1,3-propanediol derivatives, their pharmacological activity and processes for preparing 2-amino-1,3-propanediol derivatives. The typical preparation scheme is summarized below (Scheme 1A):

However, the processes described in Scheme 1 have disadvantages in that they contain many complicated steps, and they produce intermediates as oily substances or various isomeric mixtures. Consequently, it was necessary to isolate and purify the intermediate products by conventional methods such chromatography which resulted in a complicated operation and in usage of large quantities of organic solvents.
CN1765872 discloses a process for preparing fingolimod according to Scheme 1B:

However several process stages are doubtful in terms of their implementation in view of the available literature, primarily the step of preparing 3-nitro-1-p-octylphenylpropan-1-one as a key synthon of this process by reacting 3-bromo-1-p-octylphenylpropan-1-one with sodium nitrite in DMF. According to CN1765872, the reaction proceeds at room temperature with 72% yield of 3-nitro-1-p-octylphenylpropan-1-one.
The reaction of alkyl halides with metal nitrites is an important method for the preparation of nitroalkanes. As a metal nitrite, silver nitrite (Victor-Meyer reaction), potassium nitrite, or sodium nitrite (Kornblum reaction) have been frequently used. The products are reported to be a mixture of nitroalkanes and alkyl nitrites, which are then separated by distillation or chromatography.

Primary and secondary alkyl iodides and bromides as well as sulfonate esters give the corresponding nitro compounds in only very modest yields upon treatment with sodium nitrite in DMF or DMSO, due mainly to the ambident character of the nitrite anion. Indeed, an efficient scalable high-yielding procedure for preparing nitroalkanes from the corresponding alkyl halides has never appeared in the literature to date. For example, reaction of 4-(3-bromopropyl)-1,2-dimethoxybenzene with sodium nitrite in DMF at room temperature (utilizing the same reaction conditions taught by CN1765872) gave the desired nitroalkane in 54% yield only by halting the reaction at the point where nitrite ester formation was minimal and did not significantly affect the nitrosation of 1,2-dimethoxy-4-(3-nitropropyl)benzene into its corresponding nitrolic acid. Although significant amounts of starting material could be recovered, it was found that chromatographic separation of the resulting mixture was an unavoidable necessity. Other practical problems associated with the teachings of CN1765872 are the formation of 3-nitro-1-(p-octylphenyl)propan-1-ol as an oil which is difficult to operate in the production stage, moderate yields of formylation (56%) and hydrogenation (66%) steps and low overall yield (˜20%).
Therefore, there exists a need to develop a process for obtaining Fingolimod which is cost effective, is based on available reagents, is scalable with ease and is industrially feasible. We herein disclose such a process.